1. A method of creating a flexible, light weight cable comprising the steps of:
a) providing a central conductor 110;
b) growing a thin film dielectric layer 130 to the central conductor 110;
c) processing the dielectric layer 130 with an ion beam; and
d) metalizing the dielectric layer 130 with thin film metalizing technology.
2. The method of claim 1, wherein the central conductor 110 is a solid metal conductor.
3. The method of claim 1, wherein the central conductor 110 is a hollow metal conductor.
4. The method of claim 1, wherein the central conductor 110 is comprised of dielectric strands that are metalized.
5. The method of claim 1, wherein the step of metalizing includes metalizing with sputtering technology.
6. The method of claim 1, wherein the step of metalizing includes metalizing with evaporative deposition technology.
7. The method of claim 1, wherein the step of metalizing includes metalizing with cathodic arc deposition technology.
8. The method of claim 1, wherein the dielectric layer is grown to a desired thickness using electrophoretic deposition.
9. The method of claim 1, wherein the dielectric layer includes nano-diamond particles.
10. The method of claim 1, wherein the dielectric layer includes nano-graphite particles.
11. The method of claim 1, further comprising the step of:
a) adding a photoimageable mask 160 on a portion of the outer conductor; and
b) etching away the outer conductor 150 in regions which have no photoimageable mask 160 to result in a more flexible outer conductor 150.
12. The method of claim 1, further comprising the step of:
a) adding a photoimageable mask 160 on a portion of the outer conductor;
b) coating the outer conductor 150 with a piezoelectric layer 163 and
c) etching away the piezoelectric layer 163 and outer conductor 150 in regions which have no photoimageable mask 160 to result in a piezoelectric transducer cable.
13. A flexible, lightweight cable comprising:
a) a central conductor 110;
b) a thin film dielectric layer 130 coating the central conductor 110 having its surface process with an ion beam; and
c) a thin film metal coating covering the dielectric layer 130 applied with thin film metalizing technology.
14. The cable of claim 13, wherein the central conductor 110 is a solid metal conductor.
15. The cable of claim 13, wherein the central conductor 110 is a hollow metal conductor.
16. The cable of claim 13, wherein the central conductor 110 is comprised of dielectric strands that are metalized.
17. The cable of claim 13, wherein the thin film metal coating is created with sputtering technology.
18. The cable of claim 13, wherein the thin film metal coating is created with evaporative deposition technology.
19. The cable of claim 13, wherein the thin film metal coating is created with cathodic arc deposition technology.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method for treating or preventing a neurodegenerative condition in a subject in need thereof comprising administering to the subject an effective amount of a targeted TKI, wherein the targeted TKI is a compound of Formula I:
or a tautomer, or an individual isomer or a mixture of isomers thereof wherein:
Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with Rt groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6-membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1-4 Re groups;
Ring A is a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1-4 Ra groups;
Ring B is a 5- or 6-membered aryl or heteroaryl ring;
L1 is selected from NR1C(O), C(O)NR1, NR1C(O)O, NR1C(O)NR1, and OC(O)NR1;
each occurrence of Ra, Rb and Rt is independently selected from the group consisting of halo, \u2014CN, \u2014NO2, \u2014R4, \u2014OR2, \u2014NR2R3, \u2014C(O)YR2, \u2014OC(O)YR2, \u2014NR2C(O)YR2, \u2014SC(O)YR2, \u2014NR2C(\u2550S)YR2, \u2014OC(\u2550S)YR2, \u2014C(\u2550S)YR2, \u2014YC(\u2550NR3)YR2, \u2014YP(\u2550O)(YR4)(YR4), \u2014Si(R2)3, \u2014NR2SO2R2, \u2014S(O)rR2, \u2014SO2NR2R3 and \u2014NR2SO2NR2R3, wherein each Y is independently a bond, \u2014O\u2014, \u2014S\u2014 or \u2014NR3\u2014;
Re, at each occurrence, is independently selected from the group consisting of halo, \u2550O, \u2014CN, \u2014NO2, \u2014R4, \u2014OR2, \u2014NR2R3, NR2R3, \u2014C(O)YR2, \u2014OC(O)YR2, \u2014NR2C(O)YR2, \u2014SC(O)YR2, \u2014NR2C(\u2550S)YR2, \u2014OC(\u2550S)YR2, \u2014C(\u2550S)YR2, \u2014YC(\u2550NR3)YR2, \u2014YP(\u2550O)(YR4)(YR4), \u2014Si(R2)3, \u2014NR2SO2R2, \u2014S(O)rR2, \u2014SO2NR2R3 and \u2014NR2SO2NR2R3, wherein each Y is independently a bond, \u2014O\u2014, \u2014S\u2014 or \u2014NR3\u2014;
R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(O)r;
each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted;
m is 0, 1, 2, 3 or 4;
n is 2 or 3;
p is 0, 1, 2, 3, 4 or 5; and,
r is 0, 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
2. A method according to claim 1, wherein in the compound of Formula I, Ring T is:
wherein Ring E is a 5- or 6-membered unsaturated ring comprising 0-3 heteroatoms selected from O, N, and S, and s is 0, 1, 2, 3 or 4.
3. A method according to claim 1, wherein in the compound of Formula I, Ring T is a bicyclic heteroaryl ring selected from:
and s is 0, 1, 2, 3 or 4.
4. A method according to claim 1, wherein the targeted TKI is a compound of Formula II:
wherein:
Ring C is a 5- or 6-membered heterocyclic or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O)r;
Rc, at each occurrence, is independently selected from halo, \u2550O, \u2014CN, \u2014NO2, \u2014R4, \u2014OR2, \u2014NR2R3, \u2014C(O)YR2, \u2014OC(O)YR2, \u2014NR2C(O)YR2, \u2014Si(R2)3, \u2014SC(O)YR2, \u2014NR2C(\u2550S)YR2, \u2014OC(\u2550S)YR2, \u2014C(\u2550S)YR2, \u2014YC(\u2550NR3)YR2, \u2014YP(\u2550O)(YR4)(YR4), \u2014NR2SO2R2, \u2014S(O)rR2, \u2014SO2NR2R3 and \u2014NR2SO2NR2R3, wherein each Y is independently a bond, \u2014O\u2014, \u2014S\u2014 or \u2014NR3-; and,
v is 0, 1, 2, 3, 4 or 5.
5. A method according to claim 4, wherein Ring T is:
wherein Ring E is a 5- or 6-membered unsaturated ring comprising 0-3 heteroatoms selected from O, N, and S, and s is 0, 1, 2, 3 or 4.
6. A method according to claim 5, wherein Rings A and B are aryl.
7. A method according to claim 5, wherein Ring C is imidazolyl.
8. A method according to claim 7, wherein the targeted TKI is a compound selected from Formulae IIa, IIb, or IIc:
9. A method according to claim 8, wherein s is 0; m, p and v are 1; Ra and Rc are methyl; and Rb is CF3.
10. A method according to claim 1, wherein the targeted TKI is a compound of Formula III:
wherein:
Ring D represents a 5-, 6-heterocyclic or heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O)r;
L2 is (CH2)z, O(CH2)x, NR3(CH2)x, S(CH2)x or (CH2)xNR3C(O)(CH2)x in either direction;
Rd, at each occurrence, is selected from the group consisting of H, halo, \u2550O, \u2014CN, \u2014NO2, \u2014R4, \u2014OR2, \u2014NR2R3, \u2014C(O)YR2, \u2014OC(O)YR2, \u2014NR2C(O)YR2, \u2014SC(O)YR2, \u2014NR2C(\u2550S)YR2, \u2014OC(\u2550S)YR2, \u2014C(\u2550S)YR2, \u2014YC(\u2550NR3)YR2, \u2014YP(\u2550O)(YR4)(YR4), \u2014Si(R2)3, \u2014NR2SO2R2, \u2014S(O)rR2, \u2014SO2NR2R3 and \u2014NR2SO2NR2R3, wherein each Y is independently a bond, \u2014O\u2014, \u2014S\u2014 or \u2014NR3-;
R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(O)r;
each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted;
p is 0, 1, 2, 3 or 4;
w is 0, 1, 2, 3, 4 or 5;
x is 0, 1, 2 or 3; and,
z is 1, 2, 3 or 4.
11. A method according to claim 10, wherein Ring T has the following structure:
wherein Ring E is a 5- or 6-membered unsaturated ring comprising 0-3 heteroatoms selected from O, N, and S, and s is 0, 1, 2, 3 or 4.
12. A method according to claim 11, wherein Rings A and B are aryl.
13. A method according to claim 11, wherein Ring T is a bicyclic heteroaryl ring selected from:
and s is 0, 1, 2, 3 or 4.
14. A method according to claim 13, wherein Ring D is piperazinyl and L2 is CH2.
15. A method according to claim 14 wherein the targeted TKI is a compound selected from Formulae IIIa, IIIb, and IIIc:
16. A method according to claim 15 wherein s is 0, m is 1, p is 1, Ra is methyl, Rb is CF3, and Rd is methyl or \u2014CH2CH2OH.
17. A method according to claim 1, wherein the targeted TKI is a compound selected from the group consisting of:
N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo1,2-apyrazin-3-ylethynyl)-4-methylbenzamide;
3-(Imidazo1,2-apyrazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo1,2-apyrazin-3-ylethynyl)-4-methylbenzamide;
3-(Imidazo1,2-apyridin-3-ylethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo1,2-apyridin-3-ylethynyl)-4-methylbenzamide;
3-(Imidazo1,2-apyridin-3-ylethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
N-(5-tert-butylisoxazol-3-yl)-3-(imidazo1,2-apyridin-3-ylethynyl)-4-methylbenzamide;
3-(Imidazo1,2-apyridin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazo1,2-apyridin-3-ylethynyl)-4-methylbenzamide;
3-((8-Acetamidoimidazo1,2-apyridin-3-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((8-acetamidoimidazo1,2-apyridin-3-yl)ethynyl)-4-methylbenzamide;
4-Methyl-3-((8-(4-(methylsulfonyl)phenylamino)imidazo1,2-apyridin-3-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
4-methyl-3-((8-(4-sulfamoylphenylamino)imidazo1,2-apyridin-3-yl)ethynyl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide;
(R)\u2014N-(4-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo1,2-bpyridazin-3-ylethynyl)-4-methylbenzamide;
N-(3-(Imidazo1,2-bpyridazin-3-ylethynyl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide;
3-(Imidazo1,2-bpyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(3-Chloro-4-(methylpiperazin-1-yl)methyl)phenyl)-3-(imidazo1,2-bpyridazin-3-ylethynyl)-4-methylbenzamide;
N-(3-Cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(imidazo1,2-bpyridazin-3-ylethynyl)-4-methylbenzamide;
3-(Imidazo1,2-bpyridazin-3-ylethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(4-((4-(2-Hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazo1,2-bpyridazin-3-ylethynyl)-4-methylbenzamide; and
3-(Imidazo1,2-bpyridazin-3-ylethynyl)-4-methyl-N-(4-(piperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl)benzamide,
or a pharmaceutically acceptable salt thereof.
18. A method according to claim 17, wherein the targeted TKI is 3-(Imidazo1,2-bpyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide or a pharmaceutically acceptable salt thereof.
19. A method according to claim 1, wherein the neurodegenerative condition is associated with mitochondrial dysfunction and is selected from the group consisting of Friedrich’s ataxia, amyotrophic lateral sclerosis, mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), myoclonic epilepsy with ragged red fibers (MERFF), epilepsy, and Huntington’s Disease.
20. A method according to claim 1, wherein the neurodegenerative condition is a tau pathology and is selected from the group consisting of Alzheimer’s disease, progressive supranuclear palsy, Pick’s disease, corticobasal degeneration, and fronto-temporal dementia linked to chromosome 17 with parkinsonism.
21. A method accordingly to claim 1, wherein the neurodegenerative condition is multiple sclerosis.
22. A method according to claim 1, wherein the targeted TKI, or a pharmaceutically acceptable salt thereof, is administered orally or intravenously.
23. A method according to claim 1, wherein the effective amount of the targeted TKI, or a pharmaceutically acceptable salt thereof, is about 5 mg to about 80 mg.
24. A method according to claim 1, wherein the targeted TKI, or a pharmaceutically acceptable salt thereof, is administered to the subject more than one day a week or on average 4 to 7 times every 7 day period.
25. A method according to claim 24, wherein the targeted TKI, or a pharmaceutically acceptable salt thereof, is administered to the subject daily.
26. A method according to claim 25, wherein an average daily dose of 5\xb12 mg, 8\xb12 mg, 12\xb13 mg, 15\xb13 mg, 20\xb14 mg, 25\xb15 mg, 30\xb16 mg, 40\xb18 mg, 45\xb19 mg, 50\xb110 mg, or 55\xb111 mg of the targeted TKI, or a pharmaceutically acceptable salt thereof, is administered to the subject.
27. A method for treating or preventing Alzheimer’s disease in a subject in need thereof comprising administering to the subject a targeted TKI in an amount sufficient to inhibit \u03b3-secretase in the brain of the subject, wherein the targeted TKI is a compound of Formula I:
or a tautomer, or an individual isomer or a mixture of isomers thereof wherein:
Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with Rt groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6-membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1-4 Re groups;
Ring A is a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1-4 Ra groups;
Ring B is a 5- or 6-membered aryl or heteroaryl ring;
L1 is selected from NR1C(O), C(O)NR1, NR1C(O)O, NR1C(O)NR1, and OC(O)NR1;
each occurrence of Ra, Rb and Rt is independently selected from the group consisting of halo, \u2014CN, \u2014NO2, \u2014R4, \u2014OR2, \u2014NR2R3, \u2014C(O)YR2, \u2014OC(O)YR2, \u2014NR2C(O)YR2, \u2014SC(O)YR2, \u2014NR2C(\u2550S)YR2, \u2014OC(\u2550S)YR2, \u2014C(\u2550S)YR2, \u2014YC(\u2550NR3)YR2, \u2014YP(\u2550O)(YR4)(YR4), \u2014Si(R2)3, \u2014NR2SO2R2, \u2014S(O)rR2, \u2014SO2NR2R3 and \u2014NR2SO2NR2R3, wherein each Y is independently a bond, \u2014O\u2014, \u2014S\u2014 or \u2014NR3\u2014;
Re, at each occurrence, is independently selected from the group consisting of halo, \u2550O, \u2014CN, \u2014NO2, \u2014R4, \u2014OR2, \u2014NR2R3, \u2014C(O)YR2, \u2014OC(O)YR2, \u2014NR2C(O)YR2, \u2014SC(O)YR2, \u2014NR2C(\u2550S)YR2, \u2014OC(\u2550S)YR2, \u2014C(\u2550S)YR2, \u2014YC(\u2550NR3)YR2, \u2014YP(\u2550O)(YR4)(YR4), \u2014Si(R2)3, NR2SO2R2, \u2014S(O)rR2, \u2014SO2NR2R3 and \u2014NR2SO2NR2R3, wherein each Y is independently a bond, \u2014O\u2014, \u2014S\u2014 or \u2014NR3\u2014;
R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(O)r;
each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted;
m is 0, 1, 2, 3 or 4;
n is 2 or 3;
p is 0, 1, 2, 3, 4 or 5; and,
r is 0, 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
28. A pharmaceutical composition for treating or preventing a neurodegenerative condition in a subject in need thereof comprising an effective amount of a targeted TKI, wherein the targeted TKI is a compound of Formula I:
or a tautomer, or an individual isomer or a mixture of isomers thereof wherein:
Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with Rt groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6-membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1-4 Re groups;
Ring A is a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1-4 Ra groups;
Ring B is a 5- or 6-membered aryl or heteroaryl ring;
L1 is selected from NR1C(O), C(O)NR1, NR1C(O)O, NR1C(O)NR1, and OC(O)NR1;
each occurrence of Ra, Rb and Rt is independently selected from the group consisting of halo, \u2014CN, \u2014NO2, \u2014R4, \u2014OR2, \u2014NR2R3, \u2014C(O)YR2, \u2014OC(O)YR2, \u2014NR2C(O)YR2, \u2014SC(O)YR2, \u2014NR2C(\u2550S)YR2, \u2014OC(\u2550S)YR2, \u2014C(\u2550S)YR2, \u2014YC(\u2550NR3)YR2, \u2014YP(\u2550O)(YR4)(YR4), \u2014Si(R2)3, \u2014NR2SO2R2, \u2014S(O)rR2, \u2014SO2NR2R3 and \u2014NR2SO2NR2R3, wherein each Y is independently a bond, \u2014O\u2014, \u2014S\u2014 or \u2014NR3\u2014;
Re, at each occurrence, is independently selected from the group consisting of halo, \u2550O, \u2014CN, \u2014NO2, \u2014R4, \u2014OR2, \u2014NR2R3, \u2014C(O)YR2, \u2014OC(O)YR2, \u2014NR2C(O)YR2, \u2014SC(O)YR2, \u2014NR2C(\u2550S)YR2, \u2014OC(\u2550S)YR2, \u2014C(\u2550S)YR2, \u2014YC(\u2550NR3)YR2, \u2014YP(\u2550O)(YR4)(YR4), \u2014Si(R2)3, \u2014NR2SO2R2, \u2014S(O)rR2, \u2014SO2NR2R3 and \u2014NR2SO2NR2R3, wherein each Y is independently a bond, \u2014O\u2014, \u2014S\u2014 or \u2014NR3\u2014;
R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(O)r;
each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl;
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted;
m is 0, 1, 2, 3 or 4;
n is 2 or 3;
p is 0, 1, 2, 3, 4 or 5; and,
r is 0, 1 or 2;
or a pharmaceutically acceptable salt, solvate or hydrate thereof; and
a pharmaceutically acceptable carrier.